The etiology and pathogenesis of hypertension (HT) clinically and experimentally are being studied with emphasis on interactions between genetic determinants and modifying environmental factors. Both programs originated with the observation that salt (NaCl) could modify blood pressure (BP). In man, the conclusions were based on statistical evaluations of groups. In rats, a single strain was selectively bred to produce two colonies with opposite and predictable BP responses to the same salt intake. It was later found that these two strains were also sensitive or resistant, respectively, to several other hypertensinogenic stimuli. The genetic substrate was therefore assumed to operate in all "forms" of HT. Our major objective is now to elucidate the nature of the influences critical in determining differences in susceptibility to HT. All of the experiments proposed here involve these two strains of rats. We have found that BP is under multigenic control in them and we are studying biochemical mechanisms controlled by these genes. We have identified the action of one gene that controls 18-hydroxy-deoxycorticosterone, an adrenocortical hypertensinogenic mineralocorticoid. Other genes clearly involve the kidney. We will continue studying the effect on BP, renin activity, and synthesis of adrenocorticoids, of transplanting between strains (a) whole kidney (b) renal medulla and (c) adrenal cortex. We will continue to investigate a humoral factor in the HT-prone rats that might lead to a clinical test for predisposition to HT. We will continue studies of inheritance in HT. We also propose to: (a) develop strains with genetic predisposition to low and high plasma lipids to study HT-atherosclerosis interactions; (b) study possible correlation among behavior patterns, exposure to "stress", and HT; (c) investigate the influence of gonadectomy on development of HT.